The Genetics of Schizophrenia

Department of Genetics, Psychiatry, and Epidemiology, University of North Carolina, Chapel Hill, USA.
PLoS Medicine (Impact Factor: 14.43). 08/2005; 2(7):e212. DOI: 10.1371/journal.pmed.0020212
Source: PubMed


Research into the etiology of schizophrenia, particularly the possible genetic basis, has never been as interesting and as provocative as in the past three years. Sullivan looks critically at the key research.

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    • "Genetics may help to identifying the biological hallmarks of schizophrenia. The heritability of schizophrenia is around 80% (Sullivan, 2005). Thus, the analysis of the genetic variations that segregate patients vs. controls may inform the biological events that drive schizophrenia. "
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    ABSTRACT: schizophrenia is a complex mental disorder marked by severely impaired thinking, delusional thoughts, hallucinations and poor emotional responsiveness. The biological mechanisms that lead to schizophrenia may be related to the genetic background of patients. Thus, a genetic perspective may help to unravel the molecular pathways disrupted in schizophrenia. In the present work, we used a molecular pathway analysis to identify the molecular pathways associated with schizophrenia. We collected data of genetic loci previously associated with schizophrenia, identified the genes located in those positions and created the metabolic pathways that are related to those genes' products. These pathways were tested for enrichment (a number of SNPs associated with the phenotype significantly higher than expected by chance) in a sample of schizophrenic patients and controls (4,486 and 4,477, respectively). The molecular pathway that resulted from the identification of all the genes located in loci previously found to be associated with schizophrenia was found to enriched, as expected (permutated p(10(6))=9.9999e-06).We found 60 SNPs amongst 30 different genes with a strong association with schizophrenia. The genes are related to the pathways related to neurodevelopment, apoptosis, vesicle traffic, immune response and MAPk cascade. The pathway related to the toll-like receptor family seemed to play a central role in the modulation/connection of various pathways whose disruption leads to schizophrenia. This pathway is related to the innate immune system, further stressing the role of immunological-related events in increasing the risk to schizophrenia. Copyright © 2014. Published by Elsevier Inc.
    Full-text · Article · Dec 2014 · Progress in Neuro-Psychopharmacology and Biological Psychiatry
    • "In addition to these clustered positive findings, other genes in the pathway of OMR genes may play a role in schizophrenia pathology. For example, PIK4CA, which maps to 22q11, a chromosomal region consistently linked to schizophrenia through copy number variant studies (Blouin et al., 1998;DeLisi et al., 2002;Sullivan, 2005), and three PIK4CA SNPs have been significantly associated with the risk of schizophrenia in a Dutch cohort in a clinical case–control study (Jungerius et al., 2008). It is possible that aberrant phosphatidylinositol (PI) levels, in part regulated by PIK4CA, may influence the shape of neurons or oligodendrocytes through cytoskeletal regulation (Jungerius et al., 2008), thereby contributing to oligodendroglial dysfunction-induced myelin abnormalities, which contribute to the pathogenesis of schizophrenia (Davis et al., 2003;Uranova et al., 2004Uranova et al., , 2007). "
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    ABSTRACT: The neuropathological basis of schizophrenia and related psychoses remains elusive despite intensive scientific investigation. Symptoms of psychosis have been reported in a number of conditions where normal myelin development is interrupted. The nature, location, and timing of white matter pathology seem to be key factors in the development of psychosis, especially during the critical adolescent period of association area myelination. Numerous lines of evidence implicate myelin and oligodendrocyte function as critical processes that could affect neuronal connectivity, which has been implicated as a central abnormality in schizophrenia. Phenocopies of schizophrenia with a known pathological basis involving demyelination or dysmyelination may offer insights into the biology of schizophrenia itself. This article reviews the pathological changes in white matter of patients with schizophrenia, as well as demyelinating diseases associated with psychosis. In an attempt to understand the potential role of dysmyelination in schizophrenia, we outline the evidence from a number of both clinically-based and post-mortem studies that provide evidence that OMR genes are genetically associated with increased risk for schizophrenia. To further understand the implication of white matter dysfunction and dysmyelination in schizophrenia, we examine diffusion tensor imaging (DTI), which has shown volumetric and microstructural white matter differences in patients with schizophrenia. While classical clinical–neuropathological correlations have established that disruption in myelination can produce a high fidelity phenocopy of psychosis similar to schizophrenia, the role of dysmyelination in schizophrenia remains controversial.
    No preview · Article · Oct 2014 · Schizophrenia Research
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    • "Increased Cell-to-Cell Variation in the HSF1 Activation Level among NPCs Differentiated from hiPSCs Derived from Subjects Diagnosed with SZ Lastly, we examined the possibility that HSF1 activation is altered in patients with neuropsychiatric disorders that are thought to be linked to exposure to harsh prenatal environmental conditions. We used iPSCs derived from patients with SZ (Brennand et al., 2011) as a model because a number of prenatal environmental risk factors have been reported to potentially cause or contribute to SZ (Sullivan, 2005) and because abnormalities in HSF1-Hsp70 signaling have been demonstrated in SZ (see Discussion). Two independent NPC lines from four patients with SZ were employed in the experiments. "
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    ABSTRACT: Prenatal exposure of the developing brain to various environmental challenges increases susceptibility to late onset of neuropsychiatric dysfunction; still, the underlying mechanisms remain obscure. Here we show that exposure of embryos to a variety of environmental factors such as alcohol, methylmercury, and maternal seizure activates HSF1 in cerebral cortical cells. Furthermore, Hsf1 deficiency in the mouse cortex exposed in utero to subthreshold levels of these challenges causes structural abnormalities and increases seizure susceptibility after birth. In addition, we found that human neural progenitor cells differentiated from induced pluripotent stem cells derived from schizophrenia patients show higher variability in the levels of HSF1 activation induced by environmental challenges compared to controls. We propose that HSF1 plays a crucial role in the response of brain cells to prenatal environmental insults and may be a key component in the pathogenesis of late-onset neuropsychiatric disorders.
    Full-text · Article · Apr 2014 · Neuron
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